tbuckley/cabot-search huggingface dataset:
Analysis of the relationship between social determinants of health and survival outcomes in gestational trophoblastic neoplasia in the United States.
Authors: Chrissy Liu, Alecia James, Jennifer Wolf, Marcia Schmidt, Edith P. Mitchell, Rose Calixte, Camille A. Clare
Journal: Journal of Clinical Oncology (2022)

e17537 Background: Gestational trophoblastic neoplasia (GTN) is a rare disease with a reported incidence of 1 in 40,000 pregnancies. There have been no studies evaluating the impact of social determinants of health (SDH) on outcomes in GTN. This study seeks to examine the influence of social and biologic prognostic factors related to survival among women with GTN. We hypothesized that older age at diagnosis, lower household income, and marginalized, racial/ethnic groups are associated with worse prognosis. Methods: In this retrospective study, the Surveillance, Epidemiology, and End Results (SEER) database was used to identify women with GTN diagnosed from 2010-2018. Clinical-pathologic characteristics were described including initial stage of disease, presence of brain metastases at diagnosis, treatment with chemotherapy or surgery, and treatment at a Commission on Cancer (CoC) accredited center. Demographic factors were collected, including race/ethnicity, age at diagnosis, marital status, median household income, and rural or urban location. Log-logistic regression models were used to estimate the association between various prognostic factors and the odds of survival. We compared overall survival distributions across race/ethnicity using the log-rank test. Results: Of the 1,149 eligible patients (pts), 36% were non-Hispanic White (NHW), 21% non-Hispanic Black (NHB), 28% Hispanic, and 14% Other (Native American, Alaska Native, Asian, Pacific Islander). Mean age was 33.8 years (range 14-87 years). The majority was in the 21-35 age group (51%). Compared to NHW pts, Hispanic pts had over two times the odds of increased survival (OR 2.11; 95% CI 1.08-3.27; p = 0.032). NHB pts had similar survival compared to NHW pts (OR 1.06; 95% CI 0.50-1.76; p = 0.860). Poor prognostic factors demonstrating decreased odds of survival included age ≥40 years (OR 0.139; 95% CI 0.025-0.478; p &lt; 0.001) and widowed status (OR 0.09; 95% CI 0.018-0.375; p &lt; 0.001). Localized stage (OR 2.94; 95% CI 1.13-5.53; p = 0.03), the absence of brain metastases (OR 4.58; 95% CI 1.96-7.91; p = 0.002), and rural location (OR 5.62; 95% CI 1.25-15.2; p = 0.028) were significantly associated with increased odds of survival. Household income and race/ethnicity were not independent predictors of survival. Conclusions: Compared to NHW pts, Hispanic pts have an increased cause-specific survival for GTN. NHB pts and NHW pts have similar survival. Additionally, rural location was significantly associated with greater odds of survival. Further research is needed to investigate the underlying mechanisms linking race/ethnicity and survival outcomes, considering structural racism, bias, and discrimination. Our findings highlight the importance of recognizing the role of racism and SDH on health disparities and call to attention the need for addressing social inequities in GTN.
Early detection of colorectal adenocarcinoma by decoding epigenetic and DNA fragmentation fingerprints of plasma cell-free DNA.
Authors: Li Suxing, Tiancheng Han, Shunli Yang, Dan Liu, Peiyao Nie, Fang Lv, Shuying He, Ying Yang, Yulong LI, Jianing Yu, Yuanyuan Hong, Yu S. Huang, Weizhi Chen, Zhengqi Wen
Journal: Journal of Clinical Oncology (2022)

3550 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect colorectal adenocarcinoma. Methods: Plasma cfDNA sampels from 215 colorectal adenocarcinoma patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 150 cancer patients and 398 healthy individuals and the independent testing cohort includes 65 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.982 in the discovery cohort and AUC =0.9664 in the independent testing cohort. Under a specificity of 94.71% (CI: 90% - 98.82%), sensitivity was 78.46% (CI: 60% - 92.31%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect colorectal adenocarcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
Influencing factors of the recurrence after neoadjuvant therapy in HER2-positive breast cancer.
Authors: Serafin Morales Murillo, Ariadna Gasol Cud"S, Noemí Tuset Der-abrain, Alvaro Rodriguez, Ana Velasco Sanchez, Felip Vilardell, Douglas Sanchez Guzman, Carles Canosa Morales, Jordi Melé Olivé
Journal: Journal of Clinical Oncology (2022)

e12608 Background: HER2-positive breast cancer is the more suitable subtype to perform a neoadjuvant therapy with chemotherapy and antiHER2 therapy because a high pathologic response and significance survival. However, despite this high percentage of pathological responses, there are still recurrences that can affect survival. Methods: We analyze a cohort of 287 HER-2 positive breast cancer treated with neoadjuvant chemotherapy and antiHER2 therapy according to current guidelines, to find the factors that could induce a recurrence. Results: Median age was of 56 (28-89), median tumor size of 37 mm (12-140), 145 (50%) had nodal involvement, estrogen receptor positive in 152 patients (53%) and median ki67 expression of 41% (3-95). HER2 expression by inmunohistochemistry was 2+ in 83 patients (29%) and 3+ in 204 (71%). A total of 50% complete pathological response (pCR) rate was detected and 54 (18,8%) relapsed. 17 patients with pCR (12%) and 37 patients without pCR (25%) had a recurrence (OR 4,31, p: 0,003). The factors that most influenced the relapse in the group of patients with pCR were: the initial size (greater than 5 cm) 30% of relapses, the initial axillary involvement (19%) and the cases with HER2 +3 expression and estrogen receptor negative (17%). In the group without pCR, the relapse was more frequent in patients with HER2 +2 expression and estrogen receptor negative (40%), HER2 +3 expression and estrogen receptor negative (43%), initial tumor size greater than 5 cm (38%) and axillary involvement (38%). Conclusions: Although pCR continues to be the most important factor to avoid relapse, there are other factors that must be considered as determinants of relapse despite achieving a pCR. Initial size greater than 5 cm is a poor prognostic factor despite reaching a pCR with up to 30% relapses, so other adjuvant interventions should be considered after initial neoadjuvant treatment.
Combination dose finding trials for targeted/immuno oncology agents in early development: Lessons learned.
Authors: Li Zhou, Micaela Reddy, Rajendar K. Mittapalli, Jing Yang, Donghua Yin
Journal: Journal of Clinical Oncology (2022)

e13595 Background: Combination therapy is commonly evaluated in clinical development of oncology investigational agent (IA). An IA may be combined with an approved agent (AA), or with another IA. The aim of this landscape analysis was to 1) summarize and evaluate the different dose finding study design options used in early clinical development for oncology targeted/immuno therapy combinations; 2) propose best-fit application scenarios for each trial designs. Methods: The data sources included 1) FDA approved oncology combination therapies from 2010 to 2021; 2) registered early-stage oncology combination trials in the US with protocol available at clinicaltrial.gov from 2015 to mid-2021; 3) Pfizer internal programs. This analysis focused on “IA + IA” and “IA + AA” combinations. We extracted data on modality type, target, starting dose rationale, trial design and approved dose (if applicable) of the combination. Starting dose considerations and pros/cons of different trial designs were assessed. Results: Both external and internal in scope trials were summarized, including 8 approved non-Pfizer oncology combinations, 32 clinicaltrial.gov registered external trials and 14 Pfizer internal programs. Most surveyed combination trials included an AA. Selection of starting doses and dose escalation design for the combination were the two critical factors influencing the efficiency of clinical development (time, cost and resources). Overlapping toxicities are key concerns resulting in more conservative combination starting doses. The combination dose finding was generally performed with one of the following designs: sequential design, parallel (staggered) design, healthy volunteer first-in-human single ascending dose before first-in-patient combination and monotherapy lead-in (intra-patient “crossover”). A comparison of the characteristics of these dose finding designs indicate that the choice of a particular design should consider factors including exposure-response relationships for efficacy and safety of both monotherapy and combination, the benefit/risk to trial participants, study population, etc. We proposed application scenarios for each trial designs by incorporating the above considerations and analyzing the collected trial examples in the database. The dose finding for combinations between two IAs should consider additional factors including the relative contributions of the two agents to efficacy and safety, the anticipated minimal dose/exposure level for efficacy, and potential pharmacokinetic/pharmacodynamic drug-drug interactions. Conclusions: Multiple design options for dose finding exist for oncology targeted/immuno therapy combinations involving IA. The choice of a suitable design should consider properties and available data of each agents involved, trial efficiency, as well as benefit/risk of trial participants and target indication.
Role of anlotinib in the treatment of early advanced osteosarcoma of limbs in children.
Authors: Zhifan Li, Junlan Wang, Zhuoyu Wen, Zuoyao Long, Kaili Pan, Zhen Wang
Journal: Journal of Clinical Oncology (2022)

e23509 Background: The prognosis of advanced or early advanced osteosarcoma during neoadjuvant chemotherapy is unfavorable. Many patients can only accept brutal amputation without a new and reliable limb rescue solution. There are no clinical data on the efficacy and safety of anlotinib in the treatment of osteosarcoma in children and adolescents. We investigate the efficacy of anotinib plus first-line chemotherapy (platinum + doxorubicin liposome/ifosfamide) in the treatment of early advanced osteosarcoma in children and adolescents. Methods: Early advanced osteosarcoma in this study was defined as pathologically identified osteosarcoma that progressed within 6 months after radical surgery, with neoadjuvant chemotherapy or adjuvant chemotherapy. 11 cases of limb osteosarcoma with Enneking stage IIB (8 cases in the lower femur and 3 cases in the upper tibia), aged 8-15 years, were selected from February 2018 to December 2021. After 1 cycle of first-line neoadjuvant chemotherapy, patients locally advanced received anlotinib (12mg/d) combined with first-line chemotherapy for 1-2 cycles. The tumor shrinkage rate, limb salvage rate, disease-free survival time (DFS), progression-free survival time (PFS), disease control rate (DCR), and safety were analyzed. Results: 9 patients had locally advanced during neoadjuvant chemotherapy. After 2 cycles of anlotinib combined with first-line chemotherapy, the tumor shrunked and was well demarcated from surrounding tissue. All patients underwent limb salvage surgery Postoperative chemotherapy lasted for 4-6 cycles, with a median DFS of 12 months. 2 patients who developed recurrence or metastasis after radical surgery continued to complete at least 8 cycles of standard first-line chemotherapy combined with anlotinib, PFS showed separately 6 months and 8 months. The tumor shrinkage rate was 54.55% and the DCR was 72.73%. The adverse reactions associated with anlotinib were epistaxis (8 cases, 72.72%) and oral ulcer (1 case, 9.09%), which were controlled immediately after withdrawal. Conclusions: Combination of anlotinib with first-line chemotherapy can shrink the tumor, improve limb salvage rate for children with early advanced osteosarcoma, and delay disease progression for children with recurrence and metastasis after radical surgery. The toxicity of anlotinib combined with first-line chemotherapy were tolerated which is expected to be a new approach for the treatment of early advanced osteosarcoma.
The utilization of artificial intelligence to produce clinically relevant scores on PD-L1 immunostained non-small cell lung cancer biopsies.
Authors: Navi Mehra, Bhavika Patel, Stephanie Allen, Sameer S. Talwalkar, Jeppe Thagaard, Thomas W. Ramsing, Agnete Overgaard, Jeni Caldara
Journal: Journal of Clinical Oncology (2022)

e14576 Background: Immunotherapies targeting complex programmed death-ligand 1 (PD-L1) interactions have been groundbreaking in the treatment of non-small cell lung cancer (NSCLC), offering new strategies for patients who are likely to respond. PD-L1 binds to the checkpoint PD-1 to regulate T cells, which has an important role in boosting the immune response. Identifying patients who may benefit from PD-L1 focused care is dependent on the interpretation of the drug’s associated companion diagnostic (CDx) immunohistochemistry (IHC) assay. PD-L1 IHC assays stratify NSCLC patients using a Tumor Proportion Score (TPS), a manual scoring paradigm which must be applied by a clinical pathologist. Application of the score is complex as it requires the reader to visually exclude stromal and tumor-infiltrating immune cells across a full sample, retaining PD-L1 expression information for true tumor cells only. Methods: In this study, we utilized the PD-L1 [28-8] immunohistochemistry (IHC) assay to stain 10 NCSLC specimens. Stained slides were then imaged using the AT2 scanner (Leica Biosystems, Buffalo Grove, IL) scanner and analyzed using the Visiopharm Image Analysis platform. Results: The intricacy of TPS application is time consuming for the pathologist and introduces opportunity for inter- and intra-reader variability. Our novel image analysis approach utilizes artificial intelligence (AI) to automatically denote tumor nests and exclude tumor-infiltrating immune cells. The remaining true tumor cells may then be quantified for PD-L1 expression across the full biopsy, producing a TPS for each sample. Conclusions: This method allows for great accuracy and time-efficiency in providing a TPS than traditional methods, which may result in improved patient care.
28-gene classifier model for prediction of local recurrence and distant metastasis risk in HER-2 positive operable breast cancer.
Authors: Yikun Kang, Huimin Wang, Ran Ding, Binghe Xu, Peng Yuan
Journal: Journal of Clinical Oncology (2022)

e13018 Background: Accurate prediction of postoperative recurrence risk is very important for the formulation of appropriate treatment for breast cancer patients. However, traditional clinicopathological indicators cannot accurately assess the recurrence risk of patients. We aimed to build a novel gene-clinical variable model, which included 28 genetic profiles and clinical variable information, to assess the risk of recurrence in a more individualized and accurate manner. Methods: We retrospectively included a cohort of operable HER-2 positive breast cancer patients treated in Cancer Hospital of the Chinese Academy of Medical Sciences from 2010 to 2016. The genetic and clinical data were used to train and validate the 28-gene classifier model in predicting local recurrence and distant metastasis risk. Results: A total of 260 HER-2 positive breast cancer patients were Included in the study. All patients received standard adjuvant chemotherapy and routine targeted therapy after mastectomy. All patients were followed up for a median of 60.4 months for disease recurrence. Among them, 21 patients had distant metastasis events and 18 patients had local recurrence events. We used the 28 gene-clinical variable model to classify 260 patients into high- and low-risk groups. Kaplan-Meyer survival curves were used to compare the prognostic difference of DFS into high- and low- risk groups. Conclusions: 28 gene-clinical variable model may be a reliable toll to predict local recurrence and distant metastasis risk in HER-2 positive operable breast cancer.
Integrated analysis of genomic and microenvironment characteristics associated with pathology and radiology features in patients with early multifocal lung nodules.
Authors: Ben-Yuan Jiang, Wenhao Zhou, Haitao Luo
Journal: Journal of Clinical Oncology (2022)

e20519 Background: Pulmonary nodules are distinct clinical entities, and patients with different pulmonary nodules have different rates of progression to lung cancer. However, the genomic and microenvironment features of different pulmonary nodules are still unclear. Methods: 2 to 3 pulmonary nodules and matched paracancerous tissue were collected from 10 patients. Whole-exome sequencing and RNA sequencing were performed for each sample. The genomic and microenvironment characteristics were analyzed based on pathology (AIS/MIA/IA) and radiology (pGGO/mGGO/solid) features. Results: At genomic level, tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly increased with the development of the nodules. The most frequent mutation genes EGRF and KRAS were mutated exclusively. TMB and TNB in nodules with EGFR or KRAS mutation were significantly increased compared with nodules without these mutations and paracancerous. Transcriptome analysis revealed that energy metabolism signal pathways was upregulated in early stages (pGGO/AIS), while immune-related signal pathways were upregulated in latter stages (mGGO/IA). And in EGFR mutated nodules, cytokine-cytokine-receptor signal pathways were upregulated. Furter, tumor microenvironment was analyzed, and it was found that DCs, B cells and CD4+ T cells were significantly increased while endothelial and myocytes were significantly decreased with the development of the nodules. In addition, DCs were found to be significantly increased in EGFR mutated nodules when compared with KRAS mutated nodules. Conclusions: In this study, some genomic and tumor microenvironment biomarkers in different developmental stages of lung nodules were found, which may provide basis for the development of accurate diagnosis and classification of pulmonary nodules.
Real-world associations between bone-targeted agents and palliative bone radiotherapy in prostate cancer decedents: A province-wide population study.
Authors: William James Phillips, Alborz Jooya, Roshanak Mahdavi, Jennifer Leigh, Karine Tawagi, Colleen Webber, Christina Milani, Scott Carlyle Morgan, Robert Malcolm MacRae, Jean-Marc Bourque, Peter Tanuseputro, Michael Ong
Journal: Journal of Clinical Oncology (2022)

e17043 Background: Palliative bone radiation is the predominant skeletal-related event (SRE) reported in advanced prostate cancer. Bone targeted agents (BTA), such as denosumab and zoledronic acid, are shown to both prevent and delay SREs including bone radiation. This study evaluated real-world use of BTA in a large provincial database in relation to palliative bone radiotherapy prior to prostate-cancer related death. Methods: Linked, province-wide administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98646), who received continuous androgen deprivation therapy (n = 29453), died between 2013-2018 (n = 4184), and qualified for Ontario Drug Benefits (OBD; 65 years or older, n = 3788). Patients receiving novel life prolonging therapy (LPT) for metastatic castration-resistant prostate cancer (mCRPC; abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223) were selected, and use of BTA (denosumab, zoledronic acid) was identified. Demographic, health, and treatment characteristics were collected over a 2-year observation window looking back from the date of death. Multivariable analyses were conducted to identify factors important in use of palliative bone radiation. Results: 1769 patients received LPT for mCRPC, including abiraterone (n = 1094, 62%), docetaxel (n = 881, 60%), enzalutamide (n = 480, 27%), radium-223 (n = 250, 14%) and cabazitaxel (n = 108, 6%). Amongst patients receiving LPT, 57% received BTA and 60% received palliative radiation to bone. Factors associated with palliative bone radiation were receipt of BTA (OR 1.46; 95% confidence interval [CI] 1.13-1.91), metastatic disease at diagnosis (OR 1.48; CI: 1.11-1.97), radiation oncologist involvement (OR 103.11; CI: 47.03-226.25), whereas patients with fewer chronic diseases (OR 0.73; CI: 0.54-0.98) and who had prior prostatectomy (OR 0.54; CI: 0.36-0.84) were less likely to receive radiation. This relationship was maintained for both zoledronic acid (OR 1.68; CI: 1.09-2.58) and denosumab (OR 1.35, CI: 1.03-1.77). No specific LPT was associated with use of palliative bone radiation. Conclusions: Despite clinicians prescribing BTAs to prevent SREs, in this cohort, radiotherapy to bone was more likely in patients receiving BTAs. This suggests that clinicians are prescribing BTAs to patients at greater risk of SREs, but that patients dying of prostate cancer continue to have significant bone-related morbidity despite contemporary prostate cancer treatment. An analysis of primary (before bone radiotherapy) versus secondary (after bone radiotherapy) BTA prescriptions will be presented, as well as timing of BTA initiation in relation to death.